Parkinson Disease (PD) is a common, mostly sporadic neurodegenerative disease of the central and autonomic nervous systems affecting ~1 million people in the United States. Loss of substantia nigra (SN) dopaminergic neurons causes the characteristic parkinsonian movement disorder while non-motor disabilities including dementia, depression, gastrointestinal dysfunction, and autonomic instability arise from neurodegeneration in other parts of the nervous system. The cytoplasmic protein aggregates known as Lewy bodies, described nearly 100 years ago in the regions of the brain affected by PD, such as the substantia nigra, locus coeruleus, olfactory bulbs, and dorsal motor nucleus of the vagus, are considered to be the pathological hallmark of the disease. Diffuse Lewy body dementia (DLBD) accounts for ~10% of cases of all dementia, although some estimates suggest it is nearly as frequent as Alzheimer disease (AD) as a cause of dementia in the elderly. DLBD is clinically similar to AD but characteristically shows a higher frequency of psychosis with auditory and visual hallucinations and is often accompanied by the symptoms and signs of Parkinsonism. At autopsy, brains of DLBD patients have characteristic Lewy body aggregates throughout the cortex. The primary protein constituent of Lewy bodies is a-synuclein (aSyn), a 140 residue presynaptic phosphoprotein. Missense and increased copy number mutations in the gene for aSyn cause familial, autosomal dominant PD and DLBD. Since (1) aSyn-containing Lewy bodies are seen in both DLBD and PD, and (2) many of the patients in families with increased copy number mutations of aSyn have DLBD while others have PD11-15, it is very likely that the same underlying process is responsible for both conditions. The cause of most PD is unknown despite decades of research. Recently, a strong epidemological association has been found between PD/DLBD and heterozygosity for mutations in the beta-glucocerebrosidase gene (GBA), the gene in which homozygous mutations cause Gaucher disease (GD), a lysosomal storage disease. The odds ratio of finding a heterozygous GBA mutation in sporadic PD patients compared to controls ranges from the 13-28 depending on ethnic background. Thus, GBA mutations are a clear risk factor for PD but the mechanism is unknown. Being heterozygous for these mutations could increase susceptibility for PD either through haploinsufficiency of lysosomal glucocerebrosidase or through a toxic gain of function by the mutant gene product encoded by the mutant allele. The overall goal of this proposal is to develop a mouse model that uses expression of a mutant a-synuclein known to cause familial PD/DLBD to which we add either loss of function of glucocerebrosidase or expression of a mutant form of glucocerebrosidase to test for (1) changes in aSyn half-life and sensitivity to oxygen free radical challenge in cultured cells, and (2) motor and non-motor signs of PD in mice carrying pathogenic aSyn alleles and loss of function of glucocerebrosidase or expression of a mutant form of glucocerebrosidase. PUBLIC HEALTH RELEVANCE: Parkinson Disease and diffuse Lewy body dementia are common degenerative brain diseases affecting ~1 million people in the United States. The applicant wants to know if an authentic mouse model of these diseases can be created by combining genetic factors in a single mouse. These factors are the overexpression of a mutant form of 1-synuclein known to cause Parkinson disease in humans along with changes in the expression of the enzyme glucocerebrosidase, a Parkinson disease susceptibility risk factor. The ultimate goal is to create a mouse line that can be widely used to study in detail how familial Parkinson disease develops in order to identify points at which interventions could slow or stop progression of the disease.